Method for modifying amino group in molecule with the zolinium and use thereof

Abstract

The present disclosure relates to a method for modifying or marking an amino group in a molecule, wherein the amino group in the molecule is modified or marked with zolinium(s) shown in the following formula 1, wherein the molecule comprises amino acid ester, aminoamide, or peptide/protein. The method has advantages of economy and site selectivity, and has huge potential application value in the field such as pharmaceutical molecular synthesis, probe molecule and diagnostic marker reagent development.

1 . A method for modifying or labeling the amino group(s) in the molecule(s) wherein the zolinium(s) represented by the following formula 1 is used to modify or label the amino group(s) in the molecule(s), 
       
         
           
           
               
               
           
         
         In the above formula 1, 
         Ring B represents a substituted or unsubstituted 5-, 6- or 7-membered nitrogen-containing heterocyclic ring; 
         Q and U each independently represent oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) or silicon (Si); 
         R 1  represents 1-5 substituents on the ring B, which are each independently selected from hydrogen, hydroxyl, amino, mercapto, nitro, cyano, substituted or unsubstituted amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted arylamino, and halogen; or, when R 1  represents two or more substituents on the ring B, two adjacent substituents of which may connect to each other together with the atoms on the ring B to form a substituted or unsubstituted aryl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 5-7 membered heterocycloalkyl containing 1-5 atoms independently selected from oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) and silicon (Si), or a substituted or unsubstituted 5-7 membered heteroaryl containing 1-5 atoms independently selected from oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) and silicon (Si); 
         R 2  and R 3  each independently represent hydrogen, hydroxyl, amino, mercapto, nitro, cyano, substituted or unsubstituted amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted arylamino, or halogen; 
         R 4  represents hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; and 
         Y is an acid anion selected from inorganic acid ions, organic acid ions and halide ions. 
       
     
     
         2 . The method of  claim 1 , wherein,
 in formula 1,   Ring B is a 5- or 6-membered ring;   Q and U are each independently selected from oxygen, sulfur and selenium;   R 1  represents two or more substituents on ring B, two adjacent substituents of which may connect to each other together with the atoms on the ring B to form a substituted or unsubstituted aryl ring;   R 2  and R 3  are each independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl; and   R 4  is a substituted or unsubstituted alkyl.   
     
     
         3 . The method of  claim 1 , wherein, the molecule includes amino acid esters, amino amides, peptides or proteins. 
     
     
         4 . The method of  claim 1 , wherein, in the presence or absence of an additive, the zolinium(s) represented by Formula 1 reacts with the molecule(s) containing the amino group(s) in a solvent to prepare a product of which the amino group(s) is(are) labeled or modified. 
     
     
         5 . The method of  claim 4 , wherein, the method is carried out by a reaction represented by the following reaction scheme I: 
       
         
           
           
               
               
           
         
         In Reaction scheme I, in the presence or absence of an additive, the zolinium(s) represented by formula 1 reacts with the compound represented by formula 3 in a solvent to prepare a product represented by Formula 2 of which the amino group is modified, 
         wherein, in formula 3, 
         n represents an integer of 1-6; 
         R 5  represents hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; 
         Each of R 6  independently represents hydrogen, hydroxyl, amino, mercapto, nitro, cyano, substituted or unsubstituted amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted arylamino, or halogen; or 
         R 5  and R 6  connect to each other to form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) and silicon (Si); 
         W represents oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B), or silicon (Si). 
         wherein, in formula 2, ring B, R 1 , R 5 , R 6 , W, and n are defined as those in formula 1 and formula 3. 
       
     
     
         6 . The method of  claim 5 , wherein,
 n is 1 or 5;   W is oxygen or nitrogen;   R 5  is hydrogen, or a substituted or unsubstituted alkyl; and   R 6  is amino, a substituted or unsubstituted amido, a substituted or unsubstituted alkyl, or a substituted or unsubstituted phenyl.   
     
     
         7 . The method of  claim 5 , wherein, the solvent includes any one or a combination of two or more solvents of aprotic solvents and protic solvents, preferably, the solvent is n-butanol or water, and/or
 the additive includes organic bases or inorganic bases.   
     
     
         8 . Use of the zolinium(s) represented by the following formula 1 for modifying or labeling the amino group(s) in the molecule(s), 
       
         
           
           
               
               
           
         
         In the above formula 1, 
         Ring B represents a substituted or unsubstituted 5-, 6- or 7-membered nitrogen-containing heterocyclic ring; 
         Q and U each independently represent oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) or silicon (Si); 
         R 1  represents 1-5 substituents on the ring B, which are each independently selected from hydrogen, hydroxyl, amino, mercapto, nitro, cyano, substituted or unsubstituted amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted arylamino, and halogen; alternatively, when R 1  represents two or more substituents on the ring B, two adjacent substituents of which may connect to each other together with the atoms on the ring B to form a substituted or unsubstituted aryl, a substituted or unsubstituted 3-7 membered cycloalkyl, a substituted or unsubstituted 5-7 membered heterocycloalkyl containing 1-5 atoms independently selected from oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) and silicon (Si), or a substituted or unsubstituted 5-7 membered heteroaryl containing 1-5 atoms independently selected from oxygen (O), sulfur (S), selenium (Se), tellurium (Te), polonium (Po), nitrogen (N), phosphorus (P), boron (B) and silicon (Si); 
         R 2  and R 3  each independently represent hydrogen, hydroxyl, amino, mercapto, nitro, cyano, substituted or unsubstituted amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylamino, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted arylamino, or halogen; 
         R 4  represents hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; 
         Y is an acid anion selected from inorganic acid ions, organic acid ions and halide ions. 
       
     
     
         9 . Use of  claim 8 , wherein, the molecule includes amino acid esters, amino amides, peptides or proteins. 
     
     
         10 . Use of  claim 8 , wherein, the modifying or labeling is applied in fields of synthesizing pharmaceutical molecules, developing probe molecules and diagnostic labeling reagents.